Pre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma
Pre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma
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DOI：
10.1371/journal.pone.0041410
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发表时间：
2012-07-26
期刊：
影响因子：
3.7
通讯作者：
Urtti, Arto
中科院分区：
文献类型：
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作者：
Lehtinen, Julia;Raki, Mari;Urtti, Arto
背景：表皮生长因子受体（EGFR）在许多实体肿瘤类型中过表达，如卵巢癌。基于免疫脂质体的药物靶向在肿瘤给药方面显示出良好的效果。然而，应该增加肿瘤与正常组织浓度的比例，以尽量减少细胞抑制药物的不良影响。方法/主要发现：我们通过预先靶向和局部腹腔内给药的方法研究了egfr靶向的阿霉素免疫脂质体。与直接静脉（i.v.）给药脂质体相比，这种方法被用来增加肿瘤的药物递送。利用生物素-中性蛋白结合将EGFR抗体附着在聚乙二醇包被的脂质体表面。研究了受体介导的细胞摄取和egfr靶向脂质体在人卵巢腺癌（SKOV-3和SKOV3）中的细胞毒性作用。ip1)细胞。通过直接和预靶向方法以及SPECT/CT成像来探索脂质体在小鼠体内的分布。在体外实验中，靶向脂质体与卵巢癌细胞表现出高效和特异性的受体介导结合，但在细胞毒性方面，靶向和非靶向脂质体的差异仍然很小。相对较低的细胞毒性可能是由于脂质体释放阿霉素不足，而不是缺乏靶结合。在直接和预靶向给药后，靶向脂质体在体内的肿瘤摄取与非靶向脂质体相当。对于egfr靶向和非靶向脂质体，与静脉注射相比，口服给药增加了脂质体在肿瘤中的积累。结论/意义：腹腔注射脂质体可能是治疗腹腔肿瘤的有效途径。ipp预靶向方法作为一种潜在的癌症治疗方法值得进一步研究。
Background: Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs.Methodology/Principal Findings: We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro, but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections.Conclusions/Significance: Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.